Human rhinoviruses (HRV) are RNA viruses in the Enterovirus genus of the Picornavirus family, and are divided into three groups, HRV-A, HRV-B and HRV-C, based on sequence analysis. These viruses cause a variety of upper and lower respiratory tract infections (RTIs). Typically the upper RTIs are not especially serious in healthy subjects, manifesting as the common cold, but they can lead to more serious conditions such as acute otitis media and rhinosinusitis. Lower RTIs caused by HRV can be more severe, particularly in susceptible populations; for example, they can cause serious exacerbations in subjects with COPD, asthma, or cystic fibrosis, and severe, sometimes fatal pneumonia in infants, the elderly, and immunocompromised subjects.
In spite of the need for antiviral therapeutic agents to treat diseases caused by HRV, there are no approved HRV antivirals in the U.S. Mello, et al., Antimicrobial Agents and Chemotherapy, 58(3), 1546-55 (2014). Various antiviral agents with different modes of action have been tested against HRV, e.g., capsid-binding inhibitors (pleconaril, pirodavir), 3C protease inhibitors (rupintrivir), and nucleoside analogs (MK-0608, an inhibitor of 3D polymerase), and PI4K-IIIβ inhibitors (PIK93), but none have passed clinical trials. Id.
Nucleoside compounds having antiviral activity are well known in the art; for example, AZT is used to treat HIV infections. It acts as an inhibitor of reverse transcriptase, inhibiting an enzyme HIV requires in order to synthesize DNA, thus inhibiting HIV replication. Various nucleoside analogs have been shown to have activity on hepatitis C virus (HCV)—see, e.g., Smith, et al., J. Med. Chem. 52(1), 219-23 (2009); WO2012/040124; WO2011/100131; and US2012/0070415. None, however, have been developed to treat human rhinovirus infections.
One of the complications of treating HRV is the large number of different strains: over 160 strains of HRV are known, and if a therapeutic for treating HRV is not effective on most of the common strains, it would be necessary to determine which strain a patient has before treatment. That is not practical in most situations at present, so an antiviral with broad-spectrum activity on various HRV strains would be especially valuable.
Thus there remains a need for antiviral agents useful to treat HRV infections, particularly in populations susceptible to the more serious effects of HRV infection. The present invention provides such antiviral compounds and pharmaceutical compositions containing these compounds, as well as methods of using the compounds and compositions for treatment of subjects having or at risk of HRV infections.